The four D-2-amino-4,5-methano-adipates 26, 27, 32, 33 were synthesized and their biological activity at the N-methyl-D-aspartate (NMDA) receptor was assessed. The synthesis involved as a key step a rhodium acetate dimer catalyzed addition of ethyl diazoacetate to the protected D-allyglycine (17). In vitro receptor binding using L-[H-3]glutamate as the radioligand provided affinity data, while modulation of [H-3]TCP binding was used as a functional assay. The analogues were also evaluated in [H-3]kainate and [H-3]AMPA binding to assess selectivity over non-NMDA glutamate receptors. Three of the four diastereoisomer, D-CAA B (27), C (32) and D (33) were shown to have agonist properties at the NMDA-site, while the fourth, (2R,4R,5R) D-CAA A (26) was characterized as an NMDA-site atypic antagonist.
SYNTHESIS, ABSOLUTE-CONFIGURATION AND ACTIVITY AT N-METHYL-D-ASPARTIC ACID (NMDA) RECEPTOR OF THE 4 D-2-AMINO-4,5-METHANO-ADIPATE DIASTEREOISOMERS
PELLICCIARI, Roberto;NATALINI, Benedetto;MARINOZZI, Maura;
1991
Abstract
The four D-2-amino-4,5-methano-adipates 26, 27, 32, 33 were synthesized and their biological activity at the N-methyl-D-aspartate (NMDA) receptor was assessed. The synthesis involved as a key step a rhodium acetate dimer catalyzed addition of ethyl diazoacetate to the protected D-allyglycine (17). In vitro receptor binding using L-[H-3]glutamate as the radioligand provided affinity data, while modulation of [H-3]TCP binding was used as a functional assay. The analogues were also evaluated in [H-3]kainate and [H-3]AMPA binding to assess selectivity over non-NMDA glutamate receptors. Three of the four diastereoisomer, D-CAA B (27), C (32) and D (33) were shown to have agonist properties at the NMDA-site, while the fourth, (2R,4R,5R) D-CAA A (26) was characterized as an NMDA-site atypic antagonist.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
